- The presence of neurofibrillary tangles in the brain is one of the key hallmarks of Alzheimer’s disease.
- These irregular clumps of protein are closely associated with disease progression.
- Scientists have now designed a way to detect the very early stages of their development.
- They hope this discovery will pave the way for earlier diagnosis and, therefore, better response to treatment.
Scientists know that a build-up of specific proteins in the brain is associated with Alzheimer’s disease.
However, by the time these proteins have become visible in brain scans, disease progression is well underway, meaning that medications are less effective.
A new study, which appears in
“Detecting Alzheimer’s disease before irreversible neurodegeneration could improve the efficacy of available treatments,” Jennifer Bramen, PhD told Medical News Today.
Bramen, who was not involved in the study, is a senior research scientist and director of neuroimaging at the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, CA.
Two main protein structures are associated with Alzheimer’s disease:
- Amyloid-beta: As Alzheimer’s disease develops, amyloid precursor proteins clump together to create amyloid-beta plaques, which eventually disrupt how brain cells work.
- Tau: In the healthy brain, tau helps maintain the structure of neurons. In the brain of someone with Alzheimer’s disease, this protein goes awry and develops into NFTs.
Tau can become phosphorylated, meaning that phosphate groups are added to it. This is normal, but in the case of Alzheimer’s, the phosphorylation is abnormal or excessive.
Tau with abnormal phosphorylation is referred to as hyperphosphorylated, and it clumps together to form NFTs, which gradually build up inside cells, causing their death.
Studies show that increased levels of hyperphosphorylated tau are associated with worse cognitive symptoms of Alzheimer’s.
Because amyloid-beta tends to arrive on the scene earlier than NFTs, most attempts to look for early biomarkers have focused there. However, “a large percentage of people who have brain amyloid-beta deposits will never develop dementia,” explains the study’s senior author, Thomas Karikari, Ph.D.
In other words, it does not make an effective biomarker.
In contrast, levels of NFTs in the brain correlate
For these reasons, in the hunt for a new biomarker, the researchers focused on spotting early signs of NFT development.
The scientists focused on the “building blocks” of NFTs, including oligomers and protomers, which they refer to collectively as soluble tau assemblies.
Very little is known about the nature of these compounds and how they function. However, they do know that the early phase of NFTs’ development is more toxic to brain cells than the fully formed NFTs.
In their multipronged study, the researchers first successfully measured soluble tau assemblies in brain samples from people who died with Alzheimer’s. Then, they identified a pivotal stage of NFT development and phosphorylation sites that seem important for forming NFTs.
They showed that the presence of these phosphorylation sites, called p-tau-262 and p-tau-356, could predict future NFT production, making them potential biomarkers for early disease.
MNT spoke with Adrian M. Owen, PhD, chief scientific officer at Creyos, and a professor of cognitive neuroscience and imaging at the University of Western Ontario, Canada, who was not involved in the study. He explained that the scientists also “demonstrated that these early tau aggregates disrupt neuronal function in mouse brain tissue, suggesting their role in cognitive decline.”
“Our test identifies very early stages of tau tangle formation — up to a decade before any tau clumps can show up on a brain scan,” explains senior author Thomas Karikari, Ph.D.
MNT contacted Dr. Chris Vercammen, a board certified internal medicine physician and medical director at Remo Health who was not involved in the study. We asked about the value of detecting Alzheimer’s during its early phase.
“It allows doctors to start treatments and make helpful lifestyle changes sooner, which can help slow the disease’s progress, even though we can’t currently cure it.”
Owen outlined two additional important reasons why early detection is so important.
Firstly, early detection can help people plan their life. For the same reason, Owen explained, “it is equally important to accurately detect when someone is not likely to develop dementia.”
Expanding on this final point, Owen told MNT, “It can bring tremendous peace of mind — and assist with making end-of-life plans — to know that you are unlikely to be on the road to a dementing illness.”
However, Vercammen noted an important limitation of the study: “While this study offers some interesting results,” he told MNT, “it’s important to remember that the testing methods used here were based on autopsies that examined brain tissues from people who had been diagnosed with Alzheimer’s disease after their deaths.”
“So, the implications for treatments that could be used at scale in people living with the disease are still quite a way off.”
While discovering a way to detect Alzheimer’s early would be an exciting step forward in the treatment of such a challenging and devastating condition, Vercammen brings up some important ethical questions.
“How will this diagnostic information be used? Will it dictate treatment decisions, eligibility for clinical trials, or even insurance coverage?” he asked.
He worries that a positive test result in someone without symptoms is “particularly concerning” as it would cause “significant anxiety and distress for both them and their family.”
“In my opinion,” he continued, “any future diagnostic test derived from biomarkers must include robust counseling and education to ensure people understand the test’s limitations and the implications of a positive result.”
Along similar lines, Owen told MNT that it’s important to differentiate between a biomarker and a risk factor. He explained that, regardless of the biomarkers you might have, if you do not exhibit all the symptoms of dementia, you will not be diagnosed as such.
“This is important because many people assume that expensive, invasive, and time-consuming blood tests, brain scans, or other so-called ‘biomarkers’ are necessary and important for diagnosing dementia,” he said.
“Usually,” Owen continued, “these just reveal correlates of the dementing process rather than prove that someone has dementia.”
These tests will not correctly identify all people who will go on to develop dementia and may predict some will develop dementia when they do not.
Overall, despite the many caveats, this study is a step forward in our understanding of Alzheimer’s. However, only time and much more research will tell whether it truly catches the condition early in the clinic.
